Upload
jenni-paola-carvajalino
View
59
Download
1
Tags:
Embed Size (px)
DESCRIPTION
Artículo de revisión
Citation preview
Clin Pharmacokinet 2004; 43 (13): 879-923REVIEW ARTICLE 0312-5963/04/0013-0879/$31.00/0 2004 Adis Data Information BV. All rights reserved.
Clinical Pharmacology of TramadolStefan Grond and Armin SablotzkiDepartment of Anesthesia, Martin-Luther-University, Halle-Wittenberg, Germany
ContentsAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8801. Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 881
1.1 Pharmaceutical Formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8811.2 Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8811.3 Sustained-Release Preparations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8811.4 Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8841.5 Metabolism and Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8841.6 Influence of Cytochrome P450 on Biotransformation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8881.7 Stereoselective Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8891.8 Pharmacokinetic-Pharmacodynamic Modelling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8911.9 Effect of Age and Impaired Renal and Hepatic Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8921.10 Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 893
2. Pharmacodynamic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8932.1 Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8932.2 Analgesic Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8942.3 Effects on Respiration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8952.4 Haemodynamic Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8952.5 Gastrointestinal Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8962.6 Effects on Immune System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 896
3. Therapeutic Efficacy in Acute Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8963.1 Postoperative Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 896
3.1.1 Oral Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8963.1.2 Rectal Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8973.1.3 Intramuscular Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8973.1.4 Intravenous Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9003.1.5 Patient-Controlled Analgesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9013.1.6 Regional Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 902
3.2 Other Acute Pain Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9023.2.1 Trauma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9023.2.2 Abdominal Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9033.2.3 Labour . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 903
3.3 Place of Tramadol in Acute Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9034. Chronic Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 906
4.1 Cancer Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9064.1.1 Sustained-Release. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 907
4.2 Chronic Non-Cancer Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9094.2.1 Sustained-Release. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 910
4.3 Neuropathic Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9104.4 Place of Tramadol in Chronic Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 911
5. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9126. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 915
880 Grond & Sablotzki
Tramadol, a centrally acting analgesic structurally related to codeine andAbstractmorphine, consists of two enantiomers, both of which contribute to analgesicactivity via different mechanisms. (+)-Tramadol and the metabolite (+)-O-desmethyl-tramadol (M1) are agonists of the opioid receptor. (+)-Tramadolinhibits serotonin reuptake and ()-tramadol inhibits norepinephrine reuptake,enhancing inhibitory effects on pain transmission in the spinal cord. The comple-mentary and synergistic actions of the two enantiomers improve the analgesicefficacy and tolerability profile of the racemate.
Tramadol is available as drops, capsules and sustained-release formulations fororal use, suppositories for rectal use and solution for intramuscular, intravenousand subcutaneous injection. After oral administration, tramadol is rapidly andalmost completely absorbed. Sustained-release tablets release the active ingredi-ent over a period of 12 hours, reach peak concentrations after 4.9 hours and have abioavailability of 8795% compared with capsules. Tramadol is rapidly distribut-ed in the body; plasma protein binding is about 20%.
Tramadol is mainly metabolised by O- and N-demethylation and by conjuga-tion reactions forming glucuronides and sulfates. Tramadol and its metabolites aremainly excreted via the kidneys. The mean elimination half-life is about6 hours.
The O-demethylation of tramadol to M1, the main analgesic effective metabo-lite, is catalysed by cytochrome P450 (CYP) 2D6, whereas N-demethylation toM2 is catalysed by CYP2B6 and CYP3A4. The wide variability in the pharmaco-kinetic properties of tramadol can partly be ascribed to CYP polymorphism. O-and N-demethylation of tramadol as well as renal elimination are stereoselective.Pharmacokinetic-pharmacodynamic characterisation of tramadol is difficultbecause of differences between tramadol concentrations in plasma and at the siteof action, and because of pharmacodynamic interactions between the two enanti-omers of tramadol and its active metabolites.
The analgesic potency of tramadol is about 10% of that of morphine followingparenteral administration. Tramadol provides postoperative pain relief com-parable with that of pethidine, and the analgesic efficacy of tramadol can furtherbe improved by combination with a non-opioid analgesic. Tramadol may proveparticularly useful in patients with a risk of poor cardiopulmonary function, aftersurgery of the thorax or upper abdomen and when non-opioid analgesics arecontraindicated.
Tramadol is an effective and well tolerated agent to reduce pain resulting fromtrauma, renal or biliary colic and labour, and also for the management of chronicpain of malignant or nonmalignant origin, particularly neuropathic pain. Tramadolappears to produce less constipation and dependence than equianalgesic doses ofstrong opioids.
Tramadol hydrochloride (tramadol), (1RS,2RS)- effects, particularly of respiratory depression, con-stipation and abuse potential,[2] and has never been a2-[(dimethylamino)methyl]- 1 -(3-methoxyphenyl)-scheduled drug.[3] Therefore it became the mostcyclohexanol hydrochloride, is a centrally actingfrequently prescribed opioid in Germany.analgesic that is structurally related to codeine and
morphine. It was first synthesised in 1962 and has The registration of tramadol in the UK (1994),been available for pain treatment in Germany since the US (1995) and then many other countries re-1977.[1] Tramadol has a low incidence of adverse quired extensive additional preclinical and clinical
2004 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2004; 43 (13)
Tramadol 881
research and increased international interest. Recent no available pharmacokinetic data on soluble tab-studies have confirmed the unique and unusual phar- lets, but rapid absorption, similar to that of drops,macodynamic profile of this opioid, which is attrib- can be expected.utable to tramadol being a racemate. Both enanti- Following a single oral dose of 100mg, Cmax isomers and their metabolites contribute to the analge- approximately 300 g/L.[6-9,11] Plasma concentrationsic activity by means of different mechanisms.[4,5] and area under the concentration-time curve (AUC)These include binding to opioid receptors and block- increase linearly over the dose range 50400mg.[7,10]ade of both norepinephrine and serotonin reuptake. The extent of oral absorption of tramadol is almostThis duality of action has prompted the classifica- 100% and the bioavailability is 70% following ation of tramadol by the US FDA as a nontraditional single dose.[8,20-22] The difference between absorp-centrally acting analgesic. tion and bioavailability is attributed to the 2030%
first-pass metabolism.[6,8,21,22] Following multiple1. Pharmacokinetic Properties oral administration of tramadol 100mg four times
daily, Cmax is 16% higher and AUC is 36% higherthan after a single 100mg dose, indicating that oral1.1 Pharmaceutical Formulationsbioavailability increases to approximately 90100%
Tramadol is available in various pharmaceutical on multiple oral administration, possibly due to sat-forms. Ampoules contain 50mg (1mL) or 100mg urated first-pass hepatic metabolism.[12,23] The bio-(2mL) of tramadol in a solution for intravenous, availability of drops with ethanol is about the sameintramuscular or subcutaneous injection. Immedi- as that of drops without ethanol.[7] Oral administra-ate-release (IR) formulations, which normally re- tion of tramadol 100mg following a high-fat break-quire oral administration four to six times daily, are fast results in a 17% higher Cmax and a 10% highercapsules (50mg), soluble tablets (50mg to be dis- AUC than the corresponding values in fasted volun-solved in 50mL of water), drops (50mg = 0.5mL = teers.[24] This increase of the bioavailability by food20 drops or four actuations of the pump) and suppos- was not considered clinically relevant.[21,22]itories (100mg). Several sustained-release (SR) for- After rectal administration of suppositoriesmulations have been developed, which provide the 100mg, tramadol absorption begins within a fewopportunity for administration only twice daily. SR minutes (022 minutes).[11] A Cmax of 294 g/L istablets (100, 150 and 200mg) are based on a hydro- reached within 3.3 hours.[11] The absolute bioavaila-philic matrix system in which tramadol is evenly bility (77%) is higher than that after oral administra-distributed. On contact with the gastrointestinal flu- tion, probably due to a reduced first-pass metabol-id, the outer layer of the tablet swells gradually and ism after rectal administration.[11]forms a retarding gel layer. SR capsules (100, 150 Tramadol is rapidly and almost completely ab-and 200mg) contain multiple pellets of 1mm in sorbed after intramuscular injection.[17] Cmax of 166diameter consisting of a neutral core layered with g/L is reached 0.75 hours after intramuscular injec-tramadol and a membrane that controls the release. tion of 50mg.[17] Intramuscular injection and intra-In addition, a two-phase SR tablet contains 25mg of venous infusion over 30 minutes are bioequivalenttramadol for IR and 75mg of tramadol for SR. with respect to the extent of systemic availability.[17]
Cmax values of 355369 g/L are reached 0.9 and1.2 Absorption 1.1 hours after intramuscular injections of
100mg.[18] The pharmacokinetic properties of sub-The pharmacokinetic properties of tramadol arecutaneous tramadol, which is effective in post-summarised in table I. After oral administration,operative pain,[25] have not been examined.tramadol is absorbed almost completely and quite
rapidly after a lag time of 0.2 hours for drops[6,7] and1.3 Sustained-Release Preparations0.5 hours for capsules.[8] Peak plasma concentra-
tions (Cmax) are attained within 1.2 hours after oraladministration of drops[6,7] and within 1.61.9 hours SR tablets and capsules provide stable plasmaafter oral administration of capsules.[8,9] There are concentrations when administered at 12-hour inter-
2004 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2004; 43 (13)
882 Grond & Sablotzki
2004 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2004; 43 (13)
Tabl
e I.
Phar
mac
okin
etic
pro
perti
es o
f tra
mad
olPo
pula
tion
Rou
te a
nd d
ose
t max
C max
AUC
t1 /2
CLR
efer
ence
(n)(m
g)(h)
(g/L
)(g
h/
L)(h)
(mL/m
in)Vo
lunt
eers
(4)
PO (1
00)
260
(4h)
2194
5.1
10Vo
lunt
eers
(4)
PO (2
00)
575
(3.5h
)49
245.
9Vo
lunt
eers
(3)
PO (3
00)
930
(4h)
8599
5.7
Volu
ntee
rs (3
)PO
(400
)12
20 (4
.7h)
1047
35.
3Vo
lunt
eers
(10)
PO, c
apsu
les
(100)
1.9
290
2488
5.1
710
8Vo
lunt
eers
(8)
PO, e
than
ol d
rops
(100
)1.
230
823
905.
574
26
Volu
ntee
rs (1
2)PO
, dro
ps (5
0)1.
213
687
55.
083
77
Volu
ntee
rs (1
0)PR
, sup
posit
ory
(100)
3.3
294
2933
5.7
11Vo
lunt
eers
(18)
PO (1
00) [
single
dose
]1.
630
826
495.
611
0a12
Volu
ntee
rs (1
8)PO
(100
) [qid
, 1 w
eek]b
2.3
592
3679
6.7
73a
Volu
ntee
rs (1
2)PO
, cap
sule
s (10
0)1.
627
421
775.
913
Volu
ntee
rs (1
2)PO
, SR
tabl
ets
(100)
4.9
141
2119
5.7
Volu
ntee
rs (1
2)PO
, cap
sule
s (10
0) [bi
d, 5 d
ays]c
1.9
414
2970
Volu
ntee
rs (1
2)PO
, SR
tabl
ets
(100)
[bid,
5 day
s]d3.
529
326
56Vo
lunt
eers
(12)
PO, S
R ca
psul
es (5
0)5.
370
1039
6.0
14Vo
lunt
eers
(12)
PO, S
R ca
psul
es (1
00)
5.9
137
2060
6.2
14Vo
lunt
eers
(12)
PO, S
R ca
psul
es (2
00)
4.9
277
3952
5.6
14Fa
stin
g (24
)PO
, SR
caps
ules
(200
)6.
729
452
937.
215
Non
fast
ing
(24)
PO, S
R ca
psul
es (2
00)
7.0
305
5266
6.8
Fast
ing
(24)
PO, I
R ca
psul
es (2
00)
2.0
640
5826
6.1
Fast
ing
(24)
PO, S
R ta
blet
s (20
0)4.
537
555
176.
2Vo
lunt
eers
(24)
PO, I
R ca
psul
es (5
0) [qi
d, 3 d
ays]
321
5167
16Vo
lunt
eers
(24)
PO, S
R ca
psul
es (1
00) [
bid, 3
days
]27
451
68Vo
lunt
eers
(10)
IV (1
00)
409
(2h)
3709
5.2
467
8Vo
lunt
eers
(8)
IV (1
00)
394
(2h)
3490
5.2
487
6Vo
lunt
eers
(10)
IV (1
00)
418
(2h)
3775
5.7
447
11Vo
lunt
eers
(12)
IV o
ver 3
0 m
in (5
0)0.
5228
712
335.
059
47
Volu
ntee
rs (1
2)IV
ove
r 30
min
(50)
0.54
305
1332
5.5
596
17Vo
lunt
eers
(12)
IM (5
0)0.
7529
313
535.
561
3Vo
lunt
eers
(12)
IM (1
00)
0.9
355
3160
18Vo
lunt
eers
(12)
IM (1
00)
1.1
369
3250
657
5 ye
ars
(12)
PO, c
apsu
les
(100)
2.0
324
2508
6.1
793
19>
75 y
ears
(8)
PO, c
apsu
les
(100)
2.1
415
3854
7.0
491
19R
enal
insu
fficie
ncye
(21
)IV
(100
)89
478
3210
.828
019
Hep
atic
impa
irmen
tf (12
)PO
, cap
sule
s (10
0)1.
943
378
4813
.327
119
Cont
inue
d ne
xt p
age
Tramadol 883
vals. SR tablets (100, 150 and 200mg) release 100%of the active ingredient over a 12-hour period invitro.[13] The absolute bioavailability of SR tablets is67.3% relative to the intravenous reference formula-tion, indicating bioequivalence of SR tablets and IRcapsules (95.1%, 90% CI 87.8, 103.0%).[13] Thetime to Cmax (tmax) of 4.9 0.8 hours for the SRtablets (compared with 1.6 0.5 hours for IR cap-sules), the Cmax of 141.7 40.4 g/L (274.1 75.3g/L) and the mean absorption time of 4.70 0.90hours (1.09 0.56 hours) reflect the slow-releaseproperties of the SR tablets (table I).[13]
At steady state (after 48 hours of twice-dailyadministration), bioavailability of the SR tablet is87.4% (90% CI 81.3, 94.0%) relative to IR capsulesadministered with the same regimen.[13] The peak-trough fluctuation in plasma concentrations atsteady state is reduced from 121% with the IRcapsule to 66% with the SR tablet.[13] The extent ofrelative bioavailability of tramadol SR tablets after alipid-rich meal (postprandial/fasting administration)is 105.1% (90% CI 99.0, 111.5%) and within therange of 80125%.[13] Food intake has a slight influ-ence on rate of absorption, as shown by the shortertmax and higher Cmax, indicating that food causes aslight reduction in the retarding effect.[13]
The pharmacokinetic properties of SR capsulesare similar to those of SR tablets. Single doses of 50,100 and 200mg of tramadol as SR capsules produceplasma concentrations above half of Cmax (half-value duration) for 12.8, 12.9 and 13.0 hours, re-spectively.[14] There is a direct linear relationshipbetween the administered dosage and the achievedconcentration (table I).[14] Compared with with IRcapsules, bioavailability is only slightly diminished,whereas Cmax is markedly reduced and tmax in-creased (table I).[15] Compared with SR tablets200mg, SR capsules 200mg show 95% of the AUC,77% of the Cmax and 118% of the half-value dura-tion (table I), indicating enhanced retardation atalmost identical bioavailability.[15] Food intake hasno influence on plasma concentrations after admin-istration of tramadol 200mg as SR capsules.[15] Atsteady state (reached after approximately 48 hours),the bioavailability of the SR capsule 100mg every12 hours is 100% relative to IR capsules 50mg every6 hours.[16] The peak-trough fluctuation in plasma
2004 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2004; 43 (13)
Tabl
e I.
Cont
dPo
pula
tion
Rou
te a
nd d
ose
t max
C max
AUC
t1 /2
CLR
efer
ence
(n)(m
g)(h)
(g/L
)(g
h/
L)(h)
(mL/m
in)Ci
met
idin
eg 3
days
(12)
PO, c
apsu
les
(100)
1.5
364
3526
7.2
521
19
Carb
amaz
epin
eh 12
day
s (7)
PO, c
apsu
les
(100)
1.0
150
528
2.5
3809
19
aR
enal
cle
aran
ce.
bM
ultip
le d
oses
, 100
mg
qid
for 1
wee
k.
cM
ultip
le d
oses
, 100
mg
caps
ule
ever
y 12
hou
rs fo
r 5 d
ays.
dM
ultip
le d
oses
, 100
mg
caps
ule
ever
y 12
hou
rs fo
r 5 d
ays.
eR
enal
insu
fficie
ncy
with
a c
reat
inin
e cle
aran
ce o
f 30
80 m
L/m
in in
five
pat
ient
s, 1
030
mL/
min
in s
even
pat
ient
s, 5
10
mL/
min
in fo
ur p
atie
nts
and
884 Grond & Sablotzki
concentrations at steady state is reduced from 86% milk, and have been detected within 16 hours afterwith the IR capsule to 57% with the SR capsule.[16] administration.[22]
The two-phase tablet of tramadol (25mg IR plus1.5 Metabolism and Elimination75mg SR) produces a faster increase in plasma
concentration than an IR capsule of tramadol 50mg Tramadol is mainly excreted via the kidneys (ap-and an SR tablet of tramadol 100mg.[26] About 2.5 proximately 90%); the residual activity of a radioac-hours after administration of the two-phase tablet, tively labelled dose of tramadol was recovered in thethe concentrations become lower than those after the faeces.[30] In a study involving nine cholecystec-SR tablet of tramadol 100mg. tomised patients, only 1% of tramadol and its meta-
For subcutaneous, intramuscular or intrathecal bolites were eliminated via biliary excretion.[10] Atadministration, a tramadol depot system composed 30 minutes after intramuscular administration ofof monoolein and water has been developed.[27] In tramadol 50mg, tramadol concentrations in salivarats, intramuscular administration provides stable and urine considerably exceeded the plasma concen-pain relief for more than 10 hours.[27] Further inves- tration.[17] The Cmax in saliva and urine occurred attigations of this novel depot system will be of inter- nearly the same time as in plasma, and thereafter theest. plasma and saliva concentrations and the renal ex-
cretion rates decreased almost in parallel.[17] The1.4 Distribution saliva concentrations were 7- to 8-fold and the urine
concentrations 43- to 46-fold higher than the corre-Tramadol is rapidly distributed in the body, with sponding plasma concentrations.[17] The mean elimi-
a distribution half-life in the initial phase of 6 min- nation half-life is about 56 hours (table I).[6-12,17]utes, followed by a slower distribution phase with a The mean total clearance of tramadol was 467 mL/half-life of 1.7 hours.[23] The high total distribution min (approximately 28 L/h) and 710742 mL/minvolume of 306L after oral and 203L after parenteral (approximately 4344 L/h) following intravenousadministration indicates high tissue affinity; plasma and oral administration, respectively.[6,8]protein binding is about 20%.[8,23] After intravenous The main metabolic pathways of tramadol, N-injection of tramadol 100mg, plasma concentrations and O-demethylation (phase I reactions) and conju-of 612, 553, 483 and 409 g/L were measured after gation of O-demethylated compounds (phase II re-0.25, 0.5, 1 and 2 hours.[8] In a rodent model, tram- actions), were described 20 years ago.[30] Elevenadol was particularly distributed into the lungs, metabolites were known, five arising by phase Ispleen, liver, kidneys and brain.[21] reactions (M1 to M5) and six by phase II reactions
Brain peak concentrations of tramadol occur 10 (glucuronides and sulfates of M1, M4 and M5).minutes after oral administration, and those of its Tramadol is metabolised much more rapidly in ani-major active metabolite O-desmethyl-tramadol mals than in humans: 1% and 2530% of an oral(M1) 2060 minutes after oral administration.[28] In dose, respectively, are excreted unchanged in themice, the ratio tramadol/M1 in plasma was 0.51.0 urine.[30] In all species, M1 and M1 conjugates, M5throughout the measurements, whereas the ratio in and M5 conjugates, and M2 are the main metabo-brain was about ten at 10 minutes and about two lites, whereas M3, M4 and M4 conjugates are onlyfrom 20 to 50 minutes.[28] In rats, the ratio tramadol/ formed in minor quantities (table II).[30] In a studyM1 in plasma was 0.51.5, whereas the ratio in brain where a 50mg oral dose of tramadol was given towas about 15 at 10 minutes and about 47 there- 104 volunteers, mean values for tramadol, M1 andafter.[28] There appears to be preferential brain ver- M2 excretion in 24-hour urine were 12%, 15% andsus plasma distribution of tramadol over M1 in mice 4% of the administered dose, respectively.[31] How-and rats. ever, great interindividual differences were observ-
Tramadol passes the placental barrier, with um- ed in two humans after oral administration of eitherbilical venous plasma concentrations being 80% of 1.06 or 1.25 mg/kg of 14C-labelled tramadol.[30] Onematernal concentration.[29] Very small amounts volunteer produced mainly M1, M5, M1 conjugates(0.1%) of tramadol and M1 are excreted in breast and M5 conjugates, whereas the other produced
2004 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2004; 43 (13)
Tramadol 885
2004 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2004; 43 (13)
Tabl
e II.
Ex
cret
ion
of u
ncha
nged
tra
mad
ol a
nd it
s m
etab
olite
s in
the
urin
e of
hum
ans,
dog
s an
d ra
ts r
ecei
ving
oral
tra
mad
ol,
and
met
abol
ites
foun
d in
hum
an h
epat
icm
icro
som
es[30
,31,33
,34]
Anal
yte
Chem
ical s
truct
ure[3
0,33,3
4]Pe
rcen
tage
of e
ach
anal
yte
foun
dhu
man
ahu
man
bdo
gcra
tdhu
man
ehu
man
fhe
patic
gra
thdo
giTr
amad
ol25
321
0.9
12>
1082
22
M1
O-D
esm
ethy
l-tra
mad
ol10
52
915
>10
513
6M
2N
-D
esm
ethy
l-tra
mad
ol2
315
174
>10
613
6M
3N
,N
-D
ides
met
hyl-t
ram
adol
ND
0.8
210
510
ND
94
M4
O,N
,N
-Tr
ides
met
hyl-t
ram
adol
0.1
0.8
42